`
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENETECH, INC.,
`Patent Owner.
`_________
`
`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
`___________
`
`
`
`
`Before ZHENYU YANG, CHRISTOPHER G. PAULRAJ, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`
`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
`
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`ELIZABETH J. HOLLAND, ESQUIRE
`CYNTHIA HARDMAN, ESQUIRE
`Goodwin Proctor LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`
`
`
`ON BEHALF OF PATENT OWNER:
`
`
`LISA J. PIROZZOLO, ESQUIRE
`Wilmer Cutler Pickering Hale and Dorr LLP
`60 State Street
`Boston, MA 02109
`
`LAUREN V. BLAKELY, ESQUIRE
`Wilmer Cutler Pickering Hale and Dorr LLP
`950 Page Mill Road
`Palo Alto, CA 94304
`
`
`
`
`The above-entitled matter came on for hearing Tuesday, May 8, 2018,
`
`commencing at 3:30 p.m., at the U.S. Patent and Trademark Office, 600
`Dulany Street, Alexandria, Virginia.
`
`
`
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`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
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`P R O C E E D I N G S
`- - - - -
`JUDGE YANG: Please be seated. We're back again.
`
`
`(Pause.)
`
`
`JUDGE YANG: Are we on the record?
`
`
`THE COURT REPORTER: Yes, Your Honor.
`
`
`JUDGE YANG: Okay, thank you.
`
`
`Good afternoon and welcome back. So this is the consolidated
`
`
`hearing for IPR2017-01139 and 1140 between Petitioner Celltrion and
`Patent Owner Genentech. The challenged patents are 6,627,196 and
`7,371,379.
`And let's start with counsel introductions. Petitioner, please?
`
`
`MS. HOLLAND: Yes, good afternoon. I'm Elizabeth Holland
`
`
`from Goodwin Proctor, representing Celltrion, Petitioner, and with me is
`Cynthia Hardman, also from Goodwin Proctor.
`
`
`JUDGE YANG: Thank you. Welcome.
`
`
`MS. PIROZZOLO: Good afternoon. I'm Lisa Pirozzolo from
`WilmerHale for Patent Owner, Genentech, and with me is Lauren Blakely,
`also from WilmerHale, and other counsel who have appeared in the case.
`
`
`JUDGE YANG: Welcome back. Counsel are all veterans here
`before this tribunal and everybody has sat through 804 and 805, so I will not
`repeat too much, but for the sake of the record just quickly. Again, each
`party 45 minutes, Petitioner, Patent Owner, Petitioner, in that sequence.
`And all the objections to demonstratives or papers and exhibits are all under
`advisement, and identify for the record. And counsel did fantastically in the
`last session, so very good. And again no interruption when the other side is
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`presenting and object afterwards.
`
`
`And if no questions, Petitioner, would you like to reserve any
`time for rebuttal?
`
`
`MS. HOLLAND: Yes, Your Honor, 15 minutes.
`
`
`JUDGE YANG: Okay, very good. And you can start
`whenever you're ready.
`
`
`MS. HOLLAND: We're going to hand up the hard copies of
`the slides.
`(Pause.)
`
`
`JUDGE YANG: All right, you're all set.
`
`
`MS. HOLLAND: Thank you, Your Honor.
`
`
`I'd like to start out with a question that Judge Paulraj raised at
`
`
`the last hearing, which was, you know, why didn't Genentech start out with a
`three-times -- once-every-three-week regimen rather than a weekly regimen,
`the answer, Your Honor, is that we don't know the reason, but what we do
`know is that the weekly regimen was in the prior art and the question before
`the Board today is, once we know that that weekly regimen is in the prior
`art, how would the POSAs have thought to themselves how do we make this
`better? And we know POSAs were thinking about that.
`
`
`If we could look at slide 9, please?
`
`
`So this is from Patent Owner's response and we can see that
`Patent Owner admits that this was a very active area of research. As you can
`see, there were several statements in the Patent Owner response about how
`there were so many people engaged in research in ways to make this product
`and this regimen better. So regardless of what Genentech was thinking at
`the beginning of the day, by the time the weekly regimen was in the prior art
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`there were a lot of people out there trying to figure out how do we make this
`better.
`Can we look at paragraphs 89 to 90 from Exhibit 1103, which
`
`
`was Dr. Ratain's initial declaration?
`
`
`JUDGE PAULRAJ: Counsel, in the last slide you had some
`quotes, were those directly from Patent Owner's response, is that why you
`had the front cover of Patent Owner's response on that slide?
`
`
`MS. HOLLAND: Yes, Your Honor.
`
`
`JUDGE PAULRAJ: Okay.
`
`
`MS. HOLLAND: I'm sorry if that wasn't clear.
`
`
`JUDGE PAULRAJ: Okay, thank you.
`
`
`MS. HOLLAND: So Dr. Ratain gave a very self-evident
`explanation for why people of ordinary skill in the art would be looking to
`modify the regimen. And as he said in his declaration, a POSA would have
`known that many commonly administered chemotherapy drug regimens are
`used once every three weeks and the weekly trastuzumab regimen disclosed
`by Slamon was, as you know, weekly, it would have required three times as
`many infusion visits as chemotherapy alone.
`
`
`Can we go to 90, please? Again, this is from Exhibit 1103.
`
`
`So as Dr. Ratain explained, for the convenience of both patient
`and clinician, a POSA would have wanted to administer trastuzumab on the
`same schedule as chemotherapy. Again, what we believe to be a very self-
`evident proposition, but if that wasn't good enough we can look at Exhibit
`1017, the Rothenberg reference. This is actually on slide 11 as well, why
`don't we go there just to make it easier.
`
`
`This is a reference that was cited in our petition and what
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`Rothenberg says about a chemotherapy treatment is, "A once-every-three-
`week dosing regimen has the added advantage of greater patient
`convenience."
`
`
`And if we go to slide 14 -- and this is a quote from Exhibit 1118
`at 8, it's an FDA guidance. So convenience was explicitly called out by the
`FDA in its guidance as a reason why somebody would want to modify a
`dosing regimen. As we can see, the FDA says, "New dosing regimens,
`including changes in the schedule of administration, can lead to improved
`convenience." So we believe that even though we -- it is a self-evident
`proposition, there was plenty in the prior art to lead a person of ordinary skill
`in the art to want to have a more convenient trastuzumab dosing regimen,
`and not in a vacuum just more convenient, but specifically a one-every-
`three-week regimen to match up when the women were coming into the
`clinic anyway to get their chemotherapy treatments.
`
`
`JUDGE YANG: Patent Owner in the response pointed out the
`difference between maintaining dose intensity, which is a concept that
`Petitioner brought in the petition, that versus the minimum trough
`concentration, which is Patent Owner's position that for antibody dosing that
`should -- you know, one skilled in the art would follow the latter instead of
`the former, could you address that? Because I read the reply, I think it's
`around page 15, I thought you said it is irrelevant, that argument is
`irrelevant, but then I thought you also said but it's still supported. So I'm not
`sure I got it right --
`
`
`MS. HOLLAND: Sure.
`
`
`JUDGE YANG: -- if you can just help me out there.
`
`
`MS. HOLLAND: Yes. So this is the way Dr. Ratain got at the
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`issue of once a person of ordinary skill in the art said to themselves, you
`know what, I want to have a three-week dosing regimen, what do I do next?
`So Dr. Ratain says, as someone very experienced in the development of
`these regimens is, first thing I'm going to do is say I'd like to maintain dose
`intensity for this particular regimen, meaning I'd like to -- in that three-week
`interval, I would like to give the patient the same amount of drug they would
`have otherwise been getting if they got it once a week.
`
`
`And can we go to slide 18, please?
`
`
`And what Dr. Ratain showed in his declaration for this drug is
`that it was a very -- it's a very straightforward exercise. As you can see on
`the top of this chart on slide 18, there's weeks 1 through 12, in the middle
`there is the dose that is in the prior art that a patient would otherwise be
`getting, which is 4 milligrams per kilogram first week and then every week
`after that 2 milligrams per kilogram. So if you want to maintain that same
`amount of drug dose over the three-week period, which you've already
`established is your goal, you simply say, well, they were getting 8
`milligrams per kilogram in that first three-week period, I'm going to give
`them 8 milligrams per kilogram, same with the other three three-week
`periods that you can see on slide 18. They were getting 2 milligrams per
`kilogram dose, in other words 6 milligrams per kilogram over three weeks,
`so when I move to this three-week regimen I'm going to give them that same
`amount, which is 6 milligrams per kilogram.
`
`
`Then the question becomes, so this is the most, you know,
`obvious thing that I should be doing in terms of dose, but I can't stop there
`because I also need to make sure that that dose is also safe and efficacious,
`because, I think as Celltrion agrees with Patent Owner, you can't have a
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`more convenient dose if it doesn't work. So once you've determined the
`dose you're looking to administer, you want to check and make sure that it's
`going to remain efficacious not only for one week, but for the entire three-
`week period until the patient gets their next dose.
`
`
`And I think that -- if we go to slide 20, so there's no dispute
`here that everybody knew what that amount of drug in the serum needed to
`be. There needed to be a trough serum concentration, in other words the
`lowest amount of drug in the serum before getting the next dose of the drug
`had to be at least 10 micrograms per ml. So there was a target out there. So
`what Dr. Ratain says a person of ordinary skill would need to do is say, I
`have my dosing that I want to deliver to the patient once every three weeks
`and I know I need to maintain over that three-week period 10 micrograms
`per ml, let me determine whether or not I can do that with the dose I want to
`give the patient. And then -- and Dr. Ratain explained how the person of
`ordinary skill in the art would make that calculation.
`
`
`So let's go to -- see paragraph 97 of Exhibit 1103, which is Dr.
`Ratain's declaration.
`
`
`(Pause.)
`
`
`MS. HOLLAND: 1103? At 1003 -- no, 11 -- 1003, sorry.
`Thank you. So paragraph 97.
`
`
`All right. So what Dr. Ratain says is that a person of ordinary
`skill in the art would understand that there are two pieces of information
`they would need to have in order to determine whether or not this dosing
`regimen that they're interested in would actually maintain the 10 microgram
`per ml trough level of drug in the serum. And if you recall in the last
`argument, Patent Owner agreed that if there were data in the prior art from
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`which you could do the modeling that would be sufficient for reasonable
`expectation of success, and Dr. Ratain explained why that information is
`indeed available in the prior art.
`
`
`So there were two things a person of ordinary skill in the art
`would need to know in order to make this determination. First, as you can
`see from paragraph 97, the person of ordinary skill in the art would want to
`know the initial peak serum concentration provided by the lowest dose of the
`regimen, which is 6 milligram per kilogram, and then how much of that dose
`would remain in the serum when the next dose is administered three weeks
`later, and that have to do with the half-life of the drug in the serum. So if the
`prior art tells us those two things then the person of ordinary skill in the art
`is very comfortable that the regimen that they are proposing is going to
`indeed be successful. And as we've explained in our papers and as Dr.
`Ratain explained, the Pegram and Baselga references provide the
`information that's necessary for the POSA.
`
`
`So, first of all, if we want to think about the peak serum
`concentration as the first piece of data we're looking for in the prior art, we
`can go to the Pegram reference, Exhibit 1009, at page 8, table 6.
`
`
`And in table 6, Pegram gives you mean pharmacokinetic
`parameters, and one of the pieces of data that he gives is concentration,
`which is denoted as C here. So max C peak, maximum concentration at the
`peak, you can see is 113 plus or minus 35 for the people who were given
`trastuzumab alone and then it was 121 plus or minus 84 for those who were
`given an additional regimen with the trastuzumab. So this tells you that for
`those patients who were given a dose of trastuzumab that's equal to 4
`milligrams per kilogram, because that was what was being tested in Pegram,
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`you're going to have a concentration of 113 plus or minus 35.
`
`
`And then Dr. Ratain goes on to explain, since we're looking at 6
`milligrams per kilogram, not 4, which was the amount that was given in
`Pegram, you just simply multiply that by 1.5 and you come out with 169
`microgram per kilogram as the maximum peak concentration for the 6
`milligram per kilogram dose. So you have the first piece of data that you
`need as a POSA to make this calculation.
`
`
`The other piece of data you want to look for is the half-life.
`Again, if we stay in Pegram table 6, Exhibit 1009, we can see, if you move
`over two columns to the left now, it provides a half-life in days, again
`separated by trastuzumab alone or trastuzumab together with some other
`drugs being administered. And you can see that the half-life in days is given
`for the trastuzumab alone -- two different half-lives are given and I can -- let
`me explain that. The first one is for the vast majority of patients, 39 out of
`45 had a half-life of 9.2. There were certain patients who shed antigen, as
`it's called, and you've seen that concept in the papers, these are people for
`who trastuzumab doesn't work very well, unfortunately for these small group
`of patients, because they shed the antigen into their bloodstream.
`
`
`JUDGE PAULRAJ: On that point you said there's only a small
`group of patients, but doesn't Patent Owner say that it's actually a significant
`number of patients that have the shed antigens?
`
`
`MS. HOLLAND: So there's a small number of patients for
`whom the shed antigen is such a big issue that really the trastuzumab doesn't
`work for them and I think that's what we're seeing here. What I'll explain in
`a minute is that Dr. Ratain, because he was looking to the most conservative
`estimate of this that he could, included those, you know, 2.9 half-life day
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`people who were in the shed antigen group in his calculation of half-life,
`because what he wanted to do was to take the most conservative view on
`every parameter and say, if I do my calculation with the most conservative
`estimates, I'm going to be assured or at a minimum reasonably expect that
`I'm going to have an efficacious treatment.
`
`
`And if maybe we can -- I'd like to also put up on this point the
`excerpt from the deposition of Dr. Grass, who was Patent Owner's expert, so
`that's Exhibit 1120 at 113, 12 to 20.
`
`
`(Pause.)
`
`
`MS. HOLLAND: And Dr. Ratain from this data calculated for
`that reference a mean -- overall mean half-life of 9.7 days and Dr. Grass said
`he doesn't disagree with that, so that's a number we can go with for the
`Pegram reference.
`
`
`JUDGE YANG: So it goes back to what we talked in the last
`session. This is a weekly dosing half-life, my understanding is that Patent
`Owner disputes that you can actually extrapolate this sort of half-life into a
`three-weekly dosing regimen; do you have any response to that?
`
`
`MS. HOLLAND: Yes. So as I go through the calculation,
`what you'll see is that Dr. Ratain's calculation takes that three-week versus
`one-week into account, because what he says is -- we'll get there in a minute
`in terms of his using a seven-day half-life to be conservative, but once he
`does that he can say there will be no more than three half-lives -- half-lifes
`through three weeks, and I think when we get there the number will be there
`will be at least 12 and a half percent left in the serum. And that 12 and a
`half percent, as we'll see, is going to be over 10 micrograms with the dosing
`that he's proposing, which remember is not the same dosing as Pegram, it's a
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`higher dose. Pegram used 4, we're using 8 and 6.
`
`
`So let's look at Baselga, because Baselga, which is Exhibit
`1007, also talks about half-life. So let's go to 1007 at 5. And can we go in
`the lower right-hand corner, please? Thank you.
`
`
`So what you'll see again in Baselga, there's a half-life for all
`patients of 8.3. So -- and again, I don't want to go to the deposition
`necessarily on the screen, but again Dr. Grass at Exhibit 1120 at page 110,
`lines 10 to 13, agrees that that is the half-life of Baselga.
`
`
`So with this data in hand, Dr. Ratain says I want to do a
`conservative estimate, I want to make sure that I'm going to hit that
`minimum trough. So he says, you know what, I'm just going to use a week.
`These days are all -- these half-lives are all over a week, to be very
`conservative I'm going to use seven days as the half-life in my calculation.
`So he does the calculation using the seven-day half-life and the
`concentrations that we just saw from the other reference.
`
`
`Can we go to paragraph 97 from his initial declaration, Exhibit
`1003, please?
`
`
`(Pause.)
`
`
`MS. HOLLAND: And if we can go -- let's go to the -- we
`looked at the beginning already, so let's look at the end of that paragraph that
`starts with, "By focusing," it's four -- thank you -- four lines down.
`
`
`So what he explains here is that by looking only on the smaller
`maintenance dose, in other words 6 milligrams instead of the 8 milligram
`loading dose, he's using the most conservative estimate. And using that
`most conservative estimate, he opines that the prior art disclosed sufficient
`PK data from which the prediction could be made that an every-three-week
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`regimen would be effective. And indeed, when Dr. Ratain did the
`calculation, the minimum, using all these very conservative estimates, was
`21 micrograms per kilogram. So it was well over the trough that would need
`to be reached in order to assure yourself that this is going to be an
`efficacious treatment.
`
`
`Now, I want to hit next on this point of dose-dependent PK.
`And dose-dependent PK here actually makes Dr. Ratain's calculations even
`more conservative than only using the very conservative data points that he
`used, and let me explain why.
`
`
`First of all, it's clear that Dr. Ratain acknowledged that
`trastuzumab had dose-dependent PK. You saw probably five or more pages
`in Patent Owner's response blaming Dr. Ratain for not recognizing that there
`was dose-dependent PK. Of course he recognized that.
`
`
`Can we look at Exhibit 1003 again? This is his initial
`declaration, at paragraph 102.
`
`
`You see right there in the first sentence, "With respect to half-
`life, Baselga notes that trastuzumab has dose-dependent pharmacokinetics,
`meaning its elimination half-life varies with the administered dose." So Dr.
`Ratain knew that. What he explains in his declaration is that he used linear
`pharmacokinetic modeling because that was the most straightforward way to
`do this with all those conservative estimates and he was confident in that,
`because if you were going to look at the dose-dependent nature of
`trastuzumab, the numbers for the trough concentration would only get
`higher.
`So I think the best way to get at this is to look at the Watanabe
`
`
`reference, it's Exhibit 1006 at page 5. Is it the bottom one? I can't see well
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`enough with my glasses -- yes.
`
`
`So here's the Watanabe reference that's cited by Dr. Ratain and
`it's also cited in our papers, and I want to look at the data that Watanabe
`shows for administration of trastuzumab. So what you can see in the left-
`hand column is that there were four different doses administered, 1, 2, 4 and
`8, but what you can see at is that the trough level of serum for those patients
`is not linear. In other words, there was a much greater relative trough
`concentration at higher doses than lower doses. So at 1 milligram per
`kilogram it was 9, but for 8 it's all the way up at 248.
`
`
`So what we know is, this is the kind of drug whose dose
`dependency does not make it fall off like you'll see -- you'll hear from Patent
`Owner expert Dr. Grass, it's the kind of drug where the dose dependency
`actually makes it go in the other direction. So it's not that any -- it's not that
`Dr. Ratain kind of made this up; it's right there in the data in the prior art.
`
`
`JUDGE PAULRAJ: But on that point, though, how is this data
`consistent with what we see in the label itself as to the fact that half-life does
`increase when you administer higher doses?
`
`
`MS. HOLLAND: That's exactly the point: half-life does
`increase when you administer higher doses. So we're going to a dose of 8
`from a dose of 4, so the half-life is only going to get higher, meaning there's
`going to be more drug left in the serum at the end of the day. So this is all
`extremely consistent with the prior art, it's all spot-on relying on the prior
`art, and the most conservative way to look at the prior art to confirm that
`you're going to have a three-week dosing regimen with this 8 milligram
`loading dose followed by the 6 that's going to give you at least the minimum
`trough concentration of 10 micrograms per ml.
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`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
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`JUDGE YANG: I want to make sure I understand something
`
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`very fundamental, but put aside the numbers there.
`
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`MS. HOLLAND: Yes.
`
`
`JUDGE YANG: I understand and I think both parties agree
`there is the dose-dependent in terms of the higher the dose, the longer half-
`life --
`MS. HOLLAND: Yes.
`
`
`JUDGE YANG: -- I think everybody agrees on that and I am
`
`
`on board. What I am not sure because the parties do dispute is whether the
`second dose -- you have the initial dosing at whatever the amount and then
`in the prior art the second dose comes on day 7 or day 8, however you count
`it, and then the next one 14 and the third one would be 21, let's say that.
`
`
`MS. HOLLAND: Yes.
`
`
`JUDGE YANG: But Petitioner is saying this half-life would
`remain -- for this dose amount, for this say 6, whatever the dose you want to
`administer, for this amount when your follow-up, your subsequent dosing is
`at day 21, for the first boost this whole time, without anything in between,
`this half-life remains the same, is that -- do I get that right or --
`
`
`MS. HOLLAND: Yes. And I believe Dr. Ratain was actually
`asked about this at his deposition, I don't have the exact cite, but what he
`said is that, yes, as a matter of science, that's what happens here. The dose
`dependency means that the half-life will be different at different doses. It
`doesn't mean that the half-life is all over the place in a single given dose,
`that's just not scientifically how it works. And perhaps by the time I get
`back up for my rebuttal I will have found the reference in his testimony, but
`I believe indeed that that is what he said.
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`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
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`Can we see slide 23, please?
`
`
`So I think I've covered this point already essentially that a
`
`
`POSA would have understood that trastuzumab is eliminated more slowly at
`higher doses, resulting in a longer half-life. And we're administering higher
`doses here than what were administered in the prior art, so you have to think
`whatever half-life I saw in the prior art is going to be higher than that, more
`drug at the end of the day, so whatever calculation I did is at the bottom, the
`most conservative.
`
`
`I was going to make a couple more points on motivation, unless
`you have anything else you'd like to address on reasonable expectation of
`success?
`JUDGE PAULRAJ: Not at this point.
`
`
`MS. HOLLAND: So let me just go to the motivation point for
`
`
`a couple of moments then.
`
`
`I think, Judge Paulraj, you said in the previous argument that --
`and I wrote this down -- it seems intuitively strong, this proposition that you
`would want to have fewer infusions of drug, you know, once every three
`weeks versus once weekly, and I just want to point out that I think we all
`agree that that's very intuitively strong. The only person who doesn't say
`that and I believe who loses tremendous credibility because of that is Dr.
`Gelmon, their expert, because if we look at -- let's look at slide 12.
`
`
`So what I did on slide 12 is just put side-to-side what Dr.
`Gelmon's position is in this proceeding versus what she said in the prior art.
`And I'm not addressing yet this study she did in 1999 for a once-every-three-
`week dosing of trastuzumab for convenience purposes, I'm looking at
`something that's actually in the prior art. So what she says in this
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`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
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`proceeding here on behalf of Genentech is that in 1999 clinical oncologists
`would not have been motivated to change the trastuzumab regimen for
`convenience. That is a very -- a severe statement. It's not they might want
`to, it's not, well, let's look at efficacy first, it's, no, they would not be wanting
`to do that.
`And let's look at what Dr. Gelmon said in her prior art
`
`
`published papers. These are not about trastuzumab, these are about other
`cancer regimens that she was investigating. So in one of her papers where
`she's -- I just want to get the drug right -- so in the first box on the right, and
`this is from Exhibit 1103, she's looking at a four chemotherapy drug dosing
`regimen. And what she says there, that this regimen was designed to
`improve chemotherapy administration convenience. A very self-evident
`proposition, I'm surprised we're even debating this, but Dr. Gelmon herself
`says it in the prior art.
`
`
`Another reference from Dr. Gelmon, also in the prior art,
`talking about this time paclitaxel, and she's testing biweekly paclitaxel
`instead of weekly paclitaxel. And why is that Dr. Gelmon doing that?
`Because biweekly, in other words every two weeks instead of one week,
`may be more convenient. So clearly those of ordinary skill in the art as of
`1999 wanted to have fewer infusions if they could, not at the expense of
`efficacy, but if you could maintain the efficacy and you can get all your
`drugs on the same dosing regimen, that would be wonderful and optimal for
`the patients.
`JUDGE PAULRAJ: On that point, that's an interesting slide
`
`
`that you have there, but the prior art did teach weekly paclitaxel dosing and
`why -- and can you address Patent Owner's argument as to why you wouldn't
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`Case IPR2017-01140 (Patent 7,371,379 B2)
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`align it in terms of weekly instead of triweekly?
`
`
`MS. HOLLAND: I'm actually extremely happy you asked that,
`because I have a slide on it. I wanted to put it up and you reminded me. So
`let's look at slide 13.
`
`
`This is the Seidman 1998 reference that Patent Owner has been
`relying on saying, look, they were looking at weekly paclitaxel, of course
`that's what everyone in the art would have wanted to be doing, but if you
`look carefully at Seidman what it actually says was that the study of
`paclitaxel weekly was also motivated by considerations of convenience. It
`was a different kind of convenience. Do you want to sit in the chair, you
`know, for five hours and get your infusion or would it be more convenient to
`come weekly for a smaller amount of time? But again, it's all about
`convenience.
`
`
`Thank you.
`
`
`(Pause.)
`
`
`MS. PIROZZOLO: So I'd just like to quickly comment on that
`last Seidman reference, which I don't have on a slide, but I believe the
`convenience issue being addressed in that particular study was looking at a
`96-hour infusion versus a one-week treatment. So there it was not a
`difference between -- the convenience issue was this multiple-day infusion
`versus a one-week treatment, so it's not analogous to the difference between
`a three-week versus a one-week infusion.
`
`
`In terms of -- I don't want to repeat things that we covered in
`the prior proceeding, but I would like to highlight a couple of issues that are
`specific to this one. And I'll cover quickly the issue of convenience, but the
`comments that were just made and the slides put up about Dr. Gelmon, Dr.
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`Case IPR2017-01139 (Patent 6,627,196 B1)
`Case IPR2017-01140 (Patent 7,371,379 B2)
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`Gelmon's position is very much tied to the drug trastuzumab, which is the
`drug at issue in this case. And so the issue we have with the general
`citations to convenience in other contexts is that they don't consider the
`unique issues with trastuzumab, its novelty as a cancer treatment; the
`importance of serum trough concentration; the issue of shed antigen, which
`was pointed out, which was resulting in a number of patients not achieving
`adequate serum trough concentrations, because the amount of shed antigen
`was directly tied to half-life observed.
`
`
`In addition, Petitioner's use of the concept of dose density to get
`to the claimed regimen here, the 8 milligram loading dose and the 6
`milligram per kilogram weekly dose, is not grounded in the prior art, so I
`will cover that.
`
`
`And, secondly, Petitioner's simplified pharmacokinetics
`analysis cannot be supported. Petitioner acknowledged serious
`shortcomings -- Petitioner's expert acknowledged serious shortcomings in
`the prior art and what it disclosed with regards to the pharmacokinetics of
`trastuzumab, he ignored some of the data he did not understan
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